There is a growing need for home monitoring and diagnosis of body fluids for the early detection of health problems and for reducing health care costs. A handheld diagnostic device is desirable for collecting body fluids in a test channel for in situ testing with self-contained sensors and microprocessor for diagnosis. Such a handheld diagnostic devices also needs to include liquid reagent dispensing means and a renewable biosensor for repeated routine testing in a reusable test channel, which can be easily cleaned.
(1) Field of the Invention
The present invention relates to handheld body fluid diagnostic devices with liquid reagent dispensing capability.
(2) Related Art
There are a number of patents in the prior art that deal with the diagnosis of body fluids and related test sample collection methods and sensor configurations. In the following patents of interest on the diagnosis of urine, vagina fluid, and blood as well as on the collection and measurement of test samples are summarized for reference.
Urine
U.S. Pat. No. 5,739,041 by Nazareth et al. describes an urine collection and diagnostic device. The device receives urine sample directly from the urine stream and uses an assay material comprising a release medium of a visually detectable analyte binding reagent for detecting an analyte in the urine sample. The patent provides results of pregnancy test for assessing the measurement accuracy of the device. Although the device uses drainage vents to eliminate the incident of flooding to improve the reliability of test results, the flow path of the device is not an open channel type to enable cleaning and reuse of the device.
U.S. Pat. No. 5,876,952 by Shieh provides an amperometric glucose biosensor for the rapid detection of glucose in an urine sample. The glucose biosensor employs a sandwich configuration by which a reagent strip is placed between a sensing electrode and a reference electrode layer. When in contact with a drop of urine, the sensor provides current signal of the test sample for converting to units of urine glucose concentration, which has a linear relationship with the blood glucose concentration. This reagent strip-type glucose biosensor is for one time use only, not for low costs and frequent regular uses.
U.S. Pat. No. 6,027,570 by Farr, et al. discloses a method for cleaning optical surfaces which are repeatedly used in a urine analyzer. The method uses an aqueous solution of a quaternary ammonium or phosphonium salt, a non-ionic surfactant and a divalent ion. The clarity of the urine as related to the presence of white or red blood cells and epithelial cells orbacteria can be determined by measuring the refractive index of the urine sample through an optical surface. An optical surface is made of acrylic or other transparent material such as glass. The use of the cleaning solution ensures that the optic be cleaned without residue of urine sample affecting the refractive index for repeated measurements. For determining concentration values of glucose and other analytes, U.S. Pat. No. 6,087,182 by Jeng et al. developes a reagentless analysis of biological samples particularly suitable for urine. It uses spectroscopic measurements, visible and infrared light absorption spectroscopy to quantify the concentration of one or more analytes in a biological sample with mathematical techniques. The methods as described for measuring refractive index require the use of visible and infrared spectrometers which are too complex to be practical for a handheld diagnostic device. However, the methods demonstrate the feasibility of determining broad range of analytes without using reagents for diagnosis.
Vagina fluid
On testing vagina secretion, U.S. Pat. No. 6,106,461 by Roskin et al. uses a pH indicating material attached to panty liners and the like for differentiating between yeast and non yeast vaginal infections, as well as for diagnosis of bacteria, viruses and other microorganisms. The pH indicating material is of the type that provides a color indicative of the pH of the fluid in contact. The method depends on undefined quantity of absorbed vagina secretion on the panty liner and the visual comparison of observed color with a given color chart, both of which are subject to measurement and reading errors. More quantity of vaginal fluid sample is used in U.S. Pat. No. 6,174,293 by Buck et al. as it uses an absorbent media for collecting vagina fluid and then extracting the fluid for diagnostic purposes. For intra vaginal collection, the absorbent media is placed in a housing having receiving apertures prior to insertion into the vagina. The absorbent media is shaped similar to a tampon and it includes an absorbent core, which is at least partially surrounded by a porous matrix. The patent does not describe the procedures of extracting the fluid from the absorbent media and the diagnosis of the test sample. A more specific testing procedure is described in U.S. Pat. No. 6,019,734 by Parkinson, which simplifies the diagnosis of bacterial vaginosis. The simplified diagnostic kit includes a pH strip and a potassium hydroxide (“KOH”) patch for detecting bacterially derived amines. However, the kit is for one time use in a doctor's office only, not re-useable and not for self-diagnostic at a home environment.
In response to women who suffer menstrual cramps and vagina dryness, U.S. Pat. No. 6,183,428 by Kilgore describes the use of a built-in vibration mechanism in a tampon apparatus for easing the insertion of a tampon and menstrual cramps. Separately U.S. Pat. No. 6,080,118 by Blythe also describes the benefit of vagina stimulation for generating vagina fluid for testing but it does not address the requirement of containing a fixed amount of fluid sample for quantitative diagnostic measurements.
Blood
On diagnosis of blood samples, U.S. Pat. No. 5,077,199 by Basagni, et al. provides a stable unitary ready-to-use liquid reagent for determining the glucose content in blood. The liquid reagent comprises a glucose-oxidase free from catalase and a nonionic surface-active agent as a stabilizer. For increasing the shelve life, two reagents remain separated prior to mixing with a test sample. U.S. Pat. No. 5,866,352 by Vorberg develops a kit of two liquid reagent components for determining the fructosamine content related to glucose of a blood sample measured by color change. A test sample is treated to remove interfering sample components at a nearly neutral pH by a first reagent, and then to set a basic pH by a second reagent for producing color reaction. The method as described in the patent deals with pre-mixing of the first and the second reagents before adding with the test sample, The rate of change of color at an appropriate is photometrically determined and compared to that of a calibrating solution. This desirable process demonstrates the need of a diagnostic device having a dual-reagents dispensing capability.
Test Sample Collection
For testing body fluid samples in general, U.S. Pat. No. 4,981,786 by Dafforn discloses an assay device having multiple ports for transporting a fluid sample into contact with a reagent by the capillary action of a bibulous strip. The bibulous strip has one or more immunosorbing zones for controlling the volume of the fluid that traverses the immunosorbing zones. It uses a scale in a transparent window for quantifying the analyte in the test sample. The configuration as described, however, is only applicable to the delivery of the test sample by a dropper, syringe needle or the like, not for collection of test sample directly from a pool of body fluid.
In a more elaborate testing system, U.S. Pat. No. 6,066,243 by Anderson, et al. provides with a portable device having multiple removable testing modules for analyzing selected characteristics of body fluid samples. The portal diagnostic device includes sample chambers with inlet ports, sensors and electrical interface components, in situ calibration media, disposable cartridges and reagent test strips. The combination of the signal processing unit, the circuitry and module interface units enables direct utilization of the output signals of the removable modules for providing visual or printed display of the measured characteristics of the test samples. Although the device is portable, it is not as convenient as a handheld device and it does not simplify the process of collecting body fluids for testing.
Other liquid reagent dispensing means are described in the testing of medical swabs. U.S. Pat. No. 5,869,003 and 5,879,635 by Nason describe testing of medical swabs with liquid reagents. The former patent uses a dispenser cap to deliver one or more reagents to for contacting a collected specimen and causing a portion of the specimen to flow through a transfer wick to a diagnostic strip. The flow of the mixed specimen and reagent from the specimen chamber is directed by a valve to contact with a transfer wick which has multiple fingers impregnated with different reagents. The latter patent uses a dual-nib reagent dispenser for dispensing multiple reagents. The dual-nib dispenser is deformable to dispense two reagents in a manner to pre-mix the two reagents in a reagent chamber. The mixed reagents then is dispensed to contact a specimen for testing. While both of these methods provide testing means for medical swabs with multiple reagents, the amount of a reagent or mixed reagents in contact with the specimen is not controlled. Moreover, the disclosed dual-nib reagent dispenser does not have the flexibility of dispensing reagents independently into a test chamber.
Measurements of Test Sample
An in-situ testing procedure with direct contact between a test fluid and sensors without utilization of a third medium for transporting or extraction has been described in the above-mentioned U.S. Pat. No. 6,080,118 by Blythe for testing the vagina secretion. It uses a tubular probe for inserting into the vagina channel for immersing sensors in the vagina fluid for measurements. The insertable portion of a vaginal probe includes a number of fluid flow grooves and the probe is rotatable for stimulating the secretion of vaginal fluids for collection. The sensors are electronically coupled to integrated circuitry for analyzing measured data and are mounted on the surface of the vaginal probe to test a non-controlled quantity of test fluid between the sensors and the vaginal wall. The inconsistency of the volume of the test fluid can lead to significant measurement errors.
U.S. Pat. No. 5,684,296 by Hamblin describes a fiber optic liquid sensing system. The system uses a reflective-type optical sensor which has a housing with a highly polished reflector. The reflector is positioned at a distance opposed to the terminal surfaces of light emitting and a light receiving strands, which are bundled in side-by-side fashion. There are a number of apertures on the circumferencial wall of the housing for drawing in a fluid sample for optical measurements. Although the sensor housing is compact and contains all the sensor components, the configuration of the apertures may entrap air inside the housing that causes measurement errors. Because the segmented walls between the apertures hinder thorough cleaning, the sensor is non-reusable.
U.S. Pat. No. 5,206,711 by Bethold et al uses an open channel in conjunction with a fluid opacity sensor for measuring opacity of a fluid sample in a process line. To compensate for light source drift caused by temperature effect and 60 Hz line noise in the processing electronics, a reference optical pathway having the same optical system is used and a signal processing means is provided to cancel the effects of the light source drift. The width of the channel used is designed for the passage of fluid rather than for inducing a capillary effect to draw in and hold a fixed volume of sample fluid for testing. U.S. Pat. No. 6,043,878 by Gratzl et al. describes optical measurement systems for measuring optical property of a microliter size (droplet) test sample and a gas-assisted mixing system for mixing and stiring the test sample with an incoming reagent which is diffused through a membrane. The measurement systems as described do not control the height of sample droplet, therefore, the variation of droplet profile may affect the accuracy of reflective measurement by the optical sensor. Moreover, the slow diffusion of the reagent through the membrane and the required gas flow for mixing are not practical for a handheld diagnostic device.
U.S. Pat. No. 6,099,484 by Douglas et al. discloses a capillary tube for drawing body fluid from an incision and a test strip affixed to an upper end of the capillary tube for receiving the fluid. By pressing the device against the skin at the site of an incision, the test strip directly contacts body fluid emanating from the incision. To ensure that a sufficient sample size enters the tube, a drop-detecting mechanism uses either electrodes or an optical system for detecting the height of the sample drop. Similarly, U.S. Pat. No. 5,100,620 by Brenneman uses a capillary tube in conjunction with an exposed reagent pad to contact a test fluid. A vent passageway having a smaller diameter than the capillary tube is also used. Optical measurement begins as the optics system senses the start of a change in color of the reagent pad. Since both methods employ a capillary tube of small diameter (ranging from 0.01 to 0.03 inches), the fluid inside the tube cannot be washed out to clean it for repeated uses.
There are many prior art patents aim at even coverage of a blood sample on a reagent layer for testing. U.S. Pat. No. 5,047,206 by Dombrowski illustrates a reagent test strip having a cover mounted over an insoluble reagent surface for defining a capillary chamber for drawing a predetermined amount of liquid for quantitative measurement of the reflectance of the reagent surface. The capillary chamber has two open ends over the reagent surface but having no means of detecting the timing of complete filling the test chamber. Although a fixed amount of liquid sample is used, the test sample is not ensured mixed with the insoluble reagent and it requires much longer measurement time compared to that of a liquid reagent, which can be well mixed with a liquid sample.
U.S. Pat. No. 5,851,838 by Vetter et al uses a planar capillary gap for transporting a sample fluid over the top of a diagnostic test carrier. To avoid false test results caused by continuous re-diffusion of analyte out of a test area while the test reaction is in progress, the patentee uses excess sample liquid to surround the test carrier. Since the capillary gap is not closed during testing, the test is subject to measurement errors. Although each of these patents demonstrates use of a capillary tube for transporting a fluid sample over a test strip for testing, the capillary channels and test strips are manually replaced for each use. This is inconvenient and costly for use in a home diagnostic device.
Sensors suitable for use in conjunction with small spaces such as a capillary test channel are known. U.S. Pat. No. 5,335,305 by Kosa discloses fabrication methods for installing fiber optical sensors in fiber bundles fabricated from fibers that are bent with small radii. U.S. Pat. No. 5,851,838 by Vetter et al., U.S. Pat. No. 5,997,817 by Crismore et al., and U.S. Pat. No. 6,058,934 by Sullivan show various electrode matrices arranged in planar configurations. Sullivan details the use of four terminals in which voltage measuring electrodes are separated from current carrying electrodes, enabling only a low current to be drawn from a sample. The arrangement confines the measured current to the sensor chamber, thereby preventing the conductivity sensor from interfering with other sensors in the test instrument. The patentee describes the advantage of using a planar configuration to simplify the manufacturing process and enhance efficient fluidics so that the cells can be filled and washed out with a minimal volume of reagent. The size of the chip may be, for example, approximately 0.12 by 0.12 inches and can be disposed in a flow cell receptacle in a sensor housing to form one wall of a fluid flow path on which fluid flows perpendicular to the parallel arrangement of the electrodes. The width and spacing of the electrodes are not critical, each typically being 0.005 inches. The Crismore et al patent discloses the use of palladium as the electrode surface because of its resistance to oxidization and its relatively low cost. The preferable distance between electrodes is about 1.2 mm and the exposed area of an electrode need not be entirely covered with a test reagent.
Electrodes can also be used to measure pH. U.S. Pat. No. 5,573,798 by Kato relates to a pH-measuring electrode having a sensor film of metal oxide, which is sensitive to a hydrogen ion in solution. In operation, the pH-measuring electrode is immersed in the solution to be measured together with a reference electrode such as a calomel electrode or a silver-silver chloride electrode. Based on the potential difference between the two electrodes, a pH value is determined.
The combined use of an electrode system with a dry reagent layer for testing physiological fluids has been the subject of several patents on biosensors including U.S. Pat. No. 5,120,420 by Nankai et al., U.S. Pat. No. 5,264,103 by Yoshioka et al. and U.S. Pat. No. 6,004,441 by Fugiwara et al. Using blood drops as test samples for detecting glucose, the biosensors disclosed in these patents utilize an electrode system produced by screen-printing and a dry reagent layer containing an enzyme which reacts only to glucose in the blood sample. The enzyme contained in the reagent layer is dissolved in the sample liquid. According to the description contained in U.S. Pat. No. 6,004,441 by Fugiwarra et al, the electrode system of a biosensor is comprised of an electrode for measurement and a counter-electrode which functions as a reference electrode. The covering on top of the electrode system is a reagent layer which includes glucose oxidase as an enzyme and potassium ferricyanide as a mediator. When a voltage is applied between the electrodes, electric current flows in proportion to the concentration of glucose. Typical dimensions of an electrode system are 5 to 10 nm in electrode thickness and about 70. mu.m between electrodes. For better performance, the width of each of the two counter-electrodes is preferably the same or larger than that of the measuring electrode. In operation, a drop of blood is placed on the reagent layer after the electrode system is energized. After the change in conductivity stabilizes, the voltage applied is suspended for a period of time to allow for the oxidation of glucose and the reduction of potassium ferricyanide to take place. After completion of the reaction, a voltage is applied again to cause oxidation of the reduced potassium ferricyanide. This results in an electric current, which is proportional to the concentration of glucose, as a measurement of the blood sugar level.
It is well known in the prior art to cover the electrode surfaces of a biosensor with permselective membranes to separate a fluid sample from contacting the electrodes directly. The main function of a permselective membrane is to separate electrolytes for electrochemical reactions from interferants in a fluid sample that induce measurement errors. U.S. Pat. No. 5,567,290 by Vadgama uses un-plasticized polyvinyl chloride (PVC) as a membrane barrier for testing a physiological fluid. The material acts as a barrier to paracetamol and sugars but is permeable to hydrogen peroxide and oxalate for electrochemical reactions. The sensor of U.S. Pat. No. 5,531,878 by Vadgama et al. uses enzyme electrodes incorporating a microporous membrane coated with the carbonaceous material, which is known as “diamond-like carbon”. The membrane material is preferably a polycarbonate with thickness preferably less than 10 microns and porosity in the order of 0.05 to 0.01 microns. The coated membrane as an outer shield imparts high resistance to fouling when in contact with a whole blood sample. It extends the linearity of the electrode response over a substantially greater range. Its use in a biosensor enables the reagent-less analysis of an undiluted whole blood for determining the glucose concentration. U.S. Pat. No. 5,906,719 by Treloar et al. describes a permselective membrane incorporating a charged organic species, which provides a conducting path through the membrane between the electrodes of an amperometric sensor. The provision of the organic charge carrier species in the membrane enables current flow between electrodes without interposing a separate liquid or gel electrolyte layer between the electrodes and the membrane. The membrane can be formulated to have a high degree of permselectivity with the use of positively charged organic species for preventing positively charged interferants from entering the membrane. The permselective membranes as described in these patents can extend the linearity of measurement and increase the service life of the electrode sensors.
On the reuse of a biosensor, U.S. Pat. No. 5,208,147 by Kagenow et al. discloses a method for using a disposable measuring device and a conditioning fluid chamber for repeated release of fresh conditioning fluid for calibrating a sensor for measurements. However, the device requires the inconvenient step of moving the sensor to a conditioning fluid chamber to expose the sensor surface to the conditioning fluid. An improved reusable electrochemical sensor is given in U.S. Pat. No. 6,071,739 by Vadgama. The reusable sensor configuration uses a reservoir and a pumping means for dispensing a treatment liquid to a test chamber after testing a fluid sample. The treatment liquid performs cleaning and regeneration of the sensor surface for reuse. Its analyzer system with the reusable sensor utilizes two pivoted body portions having “wallet-like” construction for closing and opening the test chamber. The reusable sensor as described, however, is only for dispensing treatment liquid after closing of the test chamber, not for dispensing a reagent for mixing with a fluid sample in a controllable manner for quantitative measurements.
It is therefore an objective of this invention to provide a handheld diagnostic device having reagent dispensing capability and a renewable biosensor system for the convenience of repeated diagnostic measurements of body fluids at home. It is also an objective of this invention to provide an automatic channel cover for the closing of the test channel for controlling the mixing of a reagent with a test fluid sample for quantitative diagnosis. It is further objective of this invention to provide a dual-dispensers system for simultaneous or selective dispensing of functional fluids for broader diagnostic applications.